A noncoding RNA modulator potentiates phenylalanine metabolism in mice

doi:10.1126/science.aba4991

GSTDTAP > 气候变化

DOI	10.1126/science.aba4991
	A noncoding RNA modulator potentiates phenylalanine metabolism in mice
	Yajuan Li; Zhi Tan; Yaohua Zhang; Zhao Zhang; Qingsong Hu; Ke Liang; Yao Jun; Youqiong Ye; Yi-Chuan Li; Chunlai Li; Lan Liao; Jianming Xu; Zhen Xing; Yinghong Pan; Sujash S. Chatterjee; Tina K. Nguyen; Heidi Hsiao; Sergey D. Egranov; Nagireddy Putluri; Cristian Coarfa; David H. Hawke; Preethi H. Gunaratne; Kuang-Lei Tsai; Leng Han; Mien-Chie Hung; George A. Calin; Fares Namour; Jean-Louis Guéant; Ania C. Muntau; Nenad Blau; V. Reid Sutton; Manuel Schiff; François Feillet; Shuxing Zhang; Chunru Lin; Liuqing Yang
	2021-08-06
发表期刊	Science
出版年	2021
英文摘要	Phenylketonuria is a classic example of the benefit of newborn metabolic screening: It is a single-gene disease that can be detected at birth, and its neurological effects can be prevented by dietary therapy. Unfortunately, this is not always straightforward because the disease-causing mutations in phenylalanine hydroxylase vary between patients and affect the severity of the phenotype, such that some patients' symptoms do not fully respond to the available interventions. Li et al. identified two long noncoding RNAs, one in mice and one in humans, that interact with phenylalanine hydroxylase and modulate its function (see the Perspective by Ben-Tov Perry and Ulitsky). Administration of modified RNAs mimicking their effects ameliorated the disease phenotype in mouse models of phenylketonuria. Science , aba4991, this issue p. [662][1]; see also abj7969, p. [623][2] The functional role of long noncoding RNAs (lncRNAs) in inherited metabolic disorders, including phenylketonuria (PKU), is unknown. Here, we demonstrate that the mouse lncRNA Pair and human HULC associate with phenylalanine hydroxylase (PAH). Pair -knockout mice exhibited excessive blood phenylalanine (Phe), musty odor, hypopigmentation, growth retardation, and progressive neurological symptoms including seizures, which faithfully models human PKU. HULC depletion led to reduced PAH enzymatic activities in human induced pluripotent stem cell–differentiated hepatocytes. Mechanistically, HULC modulated the enzymatic activities of PAH by facilitating PAH-substrate and PAH-cofactor interactions. To develop a therapeutic strategy for restoring liver lncRNAs, we designed GalNAc-tagged lncRNA mimics that exhibit liver enrichment. Treatment with GalNAc- HULC mimics reduced excessive Phe in Pair −/− and Pah R408W/R408W mice and improved the Phe tolerance of these mice. [1]: /lookup/doi/10.1126/science.aba4991 [2]: /lookup/doi/10.1126/science.abj7969
领域	气候变化 ; 资源环境
URL	查看原文
引用统计	被引频次：40[WOS] [WOS记录] [WOS相关记录]
文献类型	期刊论文
条目标识符	http://119.78.100.173/C666/handle/2XK7JSWQ/335576
专题	气候变化资源环境科学
推荐引用方式 GB/T 7714	Yajuan Li,Zhi Tan,Yaohua Zhang,et al. A noncoding RNA modulator potentiates phenylalanine metabolism in mice[J]. Science,2021.
APA	Yajuan Li.,Zhi Tan.,Yaohua Zhang.,Zhao Zhang.,Qingsong Hu.,...&Liuqing Yang.(2021).A noncoding RNA modulator potentiates phenylalanine metabolism in mice.Science.
MLA	Yajuan Li,et al."A noncoding RNA modulator potentiates phenylalanine metabolism in mice".Science (2021).